Abrogation of IL-3 requirements and stimulation of hematopoietic cell proliferation in vitro and in vivo by carboxylic acids.
Short-chain fatty acids, such as butyrate and propionate, induce fetal globin gene expression and are under clinical investigation in the beta-hemoglobinopathies. Limitations of the short-chain fatty acids as therapeutics include their rapid metabolism and a tendency to induce cell growth arrest if administered for prolonged periods. In studies described here, the cellular effects of other inducers of fetal globin, phenoxyacetic acid and derivatives of short-chain fatty acids and cinnamic acids, were investigated in the human erythroid cell line K562, the IL-3 dependent multi-lineage cell line (32D), and in mice and primates. Several test compounds supported 32D cell proliferation despite a 50-fold depletion of IL-3, which resulted in growth arrest and apoptotic death in control cells. The degree of proliferation induced by certain test compounds was similar to the degree of proliferation induced by Erythropoietin and G-CSF in the cells. Eight of ten compounds induced gamma globin mRNA in K562 cells. A 2.5 to 6-fold increase in reticulocytosis was observed in vivo in mice treated with two prototype compounds. Pharmacokinetic studies of three prototype compounds demonstrated millimolar plasma concentrations after single oral doses for many hours in primates. These findings identify orally bioavailable compounds which induce gamma globin gene expression and hematopoietic cell proliferation through an activity which partially abrogates requirements for IL-3. Such compounds provide potential for oral therapeutics which stimulate proliferation of hematopoietic cells of multiple lineages, as well as inducing fetal globin.
Boosalis
M S
MS
Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA.
Ikuta
T
T
Pace
B S
BS
da Fonseca
S
S
White
G L
GL
Faller
D V
DV
Perrine
S P
SP
D000818:Animals; D002264:Carboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D007377:Interleukin-3 / Q000008:administration & dosage / Q000502:physiology*; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D010215:Papio; D014407:Tumor Cells, Cultured
D002264:Carboxylic Acids; D007377:Interleukin-3; D005914:Globins